IGFBP1 as a metabolic-neurodegenerative biomarker in spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder for which reliable metabolic biomarkers are lacking. Insulin-like growth factor binding protein 1 (IGFBP1), a stress-responsive protein regulated by insulin signaling, serves as an indicator of neurodegenerative burden. The present study aimed to measure the plasma levels of insulin, glucose, IGF1, IGF2, IGFBP1, IGFBP3 and neurofilament light chain (NfL) in patients with genetically confirmed SCA3 and age-matched controls. In addition, the association between the above molecules and clinical severity were assessed using the scale for the Assessment and Rating of Ataxia score, body mass index (BMI) and NfL levels, whereas metabolic-neurodegenerative interactions were assessed by stratifying patients by insulin tertiles. A total of 32 individuals with SCA3 and 36 age- and sex-matched controls were enrolled in the current study. The results demonstrated that patients with SCA3 exhibited markedly elevated IGFBP1, IGF2 and free IGF1 levels, as well as reduced insulin and higher glucose-to-insulin ratios, thus indicating disrupted insulin signaling. IGFBP1 was positively associated with SARA score and NfL levels and negatively associated with BMI. Notably, patients in the lowest insulin tertile (<3.65 µIU/ml) showed significantly higher IGFBP1 and NfL levels compared with the remaining groups, thus suggesting that the insulin/IGFBP1/NfL axis was associated with ataxia severity. Collectively, IGFBP1 could be a promising peripheral biomarker reflecting both metabolic and neurodegenerative processes in SCA3 and could facilitate monitoring of disease stages.